Nuclear polysubstituted[(2-nitro-1-alkenyl)-aryloxy]alkanoic acids



United States Patent'O NUCLEAR POLYSUBSTITUTED [(Z-NITRO-L ALKENYL)-ARYLOXY]ALKANOIC ACIDS,

Everett M. Schultz, Ambler, and Edward J. Cragoe,

Landsdale, Pa., assignors to Merck & Co., Inc., Rahway,

.J., a corporation of New Jersey i No Drawing. Filed Sept. 30, 1965, Ser. No. 491,818

16 Claims. (Cl. 260-471) of attachment to the benzene ring; and the salt, ester and amide derivatives thereof. The products are saluretic agents useful in the treatment of hypercholesterolemia.

The products are prepared by treating a nuclear formyl substituted phenoxyalkanoic acid with This invention relates to a new class of chemical compounds which can be described generally as [(2-nitro-l- Also, it is an object of this invention to describe a novel method of preparation for the foregoing [(2-nitrol-alkenyl)aryloxylalkanoic acids, esters and amide derivatives.

Pharmacological studies show nets are effective diuretic and saluretlc agents which can products eflectively reduce the amount of sodium and chloride ions in the body, mobilize accumulated fluids in the tissues and, in general, alleviate conditions usually associated with edema.

The [(2 nitro l alkenyl)aryloxylalkanoic acids of the invention are compounds having the following structural formula:

wherein R is a member selected from the group consisting of hydrogen and alkyl,

three to four carbon atoms between their points of attachment, for example, trimethylene, tetramethylene, 1,3- butadienylene (i.e., CH=CHCH=CH etc.; In is an integer having a value of two to four and n is an integer having a value of one to three.

A preferred embodiment of the invention relates to 3,409,661 Patented Nov. 5, 1968 the [4 (2 nitro 1 alkenyl)phenoxy] alkanoic acids having the following structural formula:

R('3=CH OC.,H1n-C0OH wherein R is lower alkyl; X and X each represent a member selected from the group consisting of halogen, lower alkyl and 1,3-butadienylene and n is an integer having a value of one to three. The foregoing class of particularly good diuretic and saluretic activity and represents a preferred subgroup of compounds within the scope of this invention.

The [(2 nitro however, it is to be understood that the hydrolysis step is an optional one which is employed only when R in the planar formulae Ia and II, infra, represents an hydrocarbyl radical and it is desired to obtain the [(Z-nitro-l-alkenyl)aryloxyJalkanoic acid product (I):

wherein R, X, m and n are as defined above; R is a member selected from the group consisting of alkyl, aryl,

Preferably, the phenoxyalkanoic acid, or a corresponding ester derivative thereof (II), with the primary amine reagent is conducted in the presence of a water-immiscible solvent system to allow for removal of the water formed during the reaction tive thereof) 'the' primary amine and the nitroalkane reactants may be employed but it has excesses of amine and nitroalkane may also be used with good results. Also, it is most advantageous to add a molar excess of a substantially anhydrous lower alkanoic acid, such as glacial acetic acid, to the reaction mixture containing the nitroalkane reactant. The reaction mixture may then be heated to boiling for a short period, cooled and then poured over ice water to precipitate the desired [(2-nitro-1-alkenyl)-aryloxy]alkanoic acid or the corresponding ester derivative thereof.

The hydrolysis step is'advantageously conducted in an aqueous medium containing a catalytic amount of 'an acid such as a mineral acid, for example, hydrochloric acid, etc. Also, it is advantageous to employ a solvent in which the ester is reasonably soluble such as a lower alkanoic acid, for example, acetic acid, etc. The hydrolysis may be conducted at ambient temperatures but, generally, it is most advantageous to carry out the hydrolysis at elevated temperatures such as at 50 C. to the reflux temperature of the reaction mixture.

The formyl substituted phenoxyalkanoic acids and their corresponding ester derivatives (11) which are employed as starting materials in the aforementioned reaction with a primary amine and nitroalkane or an appropriate aryl substituted nitroalkane, may be prepared by several alternate routes. However, inasmuch as the methods for the preparation of the ester derivatives (IIc, infra) differ somewhat from the methods for the preparation of the corresponding acids (Ila, infra), the various synthetic routes for their preparation will be discussed separately.

The'formyl substituted phenoxyalkanoic acid starting materials (Ila) are conveniently prepared from their corresponding nuclear hydroxy substituted benzaldehyde precursors (III, infra) by the reaction of the latter with an appropriate etherification reagent.

When, for example, it is desired to prepare a formyl substituted phenoxyalkanoic acid (Ila) wherein the alkylene chain and the alkanoic acid moiety have one or three linear carbon atoms in the chain between the carboxy and oxygen radicals, the etherification reagent is an haloalkanoic acid having the following formula:

wherein X is halogen, for example, chlorine, bromine, iodine, etc. and Y is methylene, trimethylene, ethylidene, etc. In general, the etherification is conducted in the presence of a base such as an aqueous solution of sodium or potassium carbonate or in the presence of the corresponding hydroxide or in the presence of a sodium alcoholate such as sodium ethoxide, and the alkanoic acid salt thus obtained is then converted to the desired formyl substituted phenoxyalkanoic acid derivative (Ha) in the conventional manner by treatment with an acid such as hydrochloric acid. The following equation illustrates the reaction:

wherein X, X Y and m are defined above and PH is the cation derived from an organic or inorganic acid such as hydrochloric acid, etc. The choice of a suitable reaction solvent for the process is dependent largely upon the character of the reactants employed; however, in general, it can be stated that any solvent which is substantially inert with respect to the reactants and in which the rebeen found that slight agents are reasonably soluble,

may be usedfSolvents which have proved to be particularly advantageous include ethanol and dimethylformamide. Also the reaction may be carried out at ambient temperature but, generally, it is most desirable to conduct the reaction at temperatures slightly above ambient temperature.

Those tormyl substituted phenoxyalkanoic acids starting materials (11b, infra) wherein the alkylene chain contains two linear carbon atoms between the carboxy and oxygen moieties are prepared from their corresponding nuclear hydroxy substituted benzaldehyde precursors (III) by the reaction of the latter with propiolactone or with an appropriately substituted propiolactone, in the presence of a base such as an aqueous solution of sodium hydroxide, preferably, while heating the solution at reflux temperatures; followed by the acidification of the carboxylate intermediate thus formed to the corresponding formyl substituted phenoxyalkanoic acid (11b). The following equation illustrates the reaction:

shown by the following equation:

wherein X, m and n are as defined above and R is an hydrocarbyl radical, for example, alkyl, etc.

The formyl substituted phenoxyalkanoie acid esters (Ilc) which are also employed as starting materials in the preparation of the [(2 nitro 1 alkenyl)aryloxy] alkanoic acid products (I) of the invention may also be prepared by either of three alternate routes: (a) by the etherification of an appropriate nuclear hydroxy substituted benzaldehyde (III); (b) by the esterification of a formyl substituted phenoxyalkanoic acid (11b); or (c) by the formylation of a phenoxyalkanoic acid ester (V, infra).

The etherification process (a) for the preparation of the formyl substituted phenoxyalkanoic acid esters is conducted in a manner similar to that described above for Base IId

preparation of formyl substituted aryloxyacetic and butyric acid esters, including the branched chain derivatives thereof such as the 2-(formyl substituted phenoxy) propionic acid esters, etc.

The esterification process (b) for the preparation of the formyl substituted phenoxyalkanoic acid esters (He) is effected by the reaction of an appropriate formyl substituted phenoxyalkanoic acid (IIe) with an appropriate lower alkanol, etc. in the presence of a catalyst, such as a mineral acid or boron trifluoride, to obtain the corresponding esterified product; or, alternatively, by the reaction of a formyl substituted phenoxyalkanoic acid (112) with a suitable reagent to form the corresponding acid halide and then treating the said formyl substituted phenoxyalkanoic acid halide (IV, infra) thus formed with the lower alkanol reagent, etc. to prepare the corresponding esterified product (He). The following equation illustrates those methods of preparation:

0o.,H2noooR OHZO H01 )m 01cm ocnmnoooni Hexamethylenel tetrarnine H01 1 OCH O-CnH2nCOOR wherein R X, m and n are as defined above.

The nuclear hydroxy substituted benzaldehyde intermediates (III) are either known compounds or may be prepared by methods which are known to those skilled in the art. Thus, for example, by treating a phenol or appropriate nuclear substituted derivative thereof with chloroform m the presence of an aqueous solution of a base and then treating the resulting mixture with an acid such as hydrochloric acid, the corresponding nuclear hydroxy substituted benzaldehyde is obtained. Alternatively, the said hydroxy substituted benzaldehyde intermediates may also be obtained by the reaction of a phenol, or appropriate nuclear substituted derivative thereof, with hydrogen cyanide and hydrogen chl0ride(gas) in the presence of anhydrous aluminum chloride. This reaction is preferably conducted in an inert solvent as, for example, in a benzene solution. The following equation illustrates these methods of preparation:

CH Base/H2O Acid OH 01101; -OH

Illa

HON H01 (gas) (X)... 0 on Illa wherein X and m are as defined above.

The [(2 nitro 1 alkenyl)aryloxy]alkanoic acids and their ester derivatives are generally obtained as crystalline solids and, if desired, may be purified by recrystallization from a suitable solvent. Suitable solvents include, for example, methanol, ethanol, cyclohexane, etc. or mixtures of solvents such as a mixture of acetic acid and water or a mixture of ethanol, water and benzene, etc.

Included within the scope of this invention are the nontoxic, pharmacologically acceptable acid addition salts of the instant products (I). In general, any base which will form an acid addition salt with the [(Z-nitro-lalkenyl) aryloxyl]alkanoic acids (1) and whose pharmacological properties will not cause an adverse physiological effect when ingested by the body system is considered as being within the scope of this invention; suitable bases include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, etc., ammonia, primary, secondary and tertiary amines as monoalkylamines, dialkylamines, trialkylamines, nitrogen containing heterocyclic amines, for example, piperidine, etc.

Also included within the scope of this invention are the amide derivatives of the [(2-nitro-l-alkenyl)aryloxy1- alkanoic acids (I) which may be prepared by several methods. According to one method, the amide derivatives are prepared by converting a [(2-nitro-1-alkenyl)aryloxy] alkanoic acid (I) to the corresponding acid halide in a conventional manner and treating the said acid halide with ammonia or an appropriate amine to obtain the desired amide. These and other equivalent methods for the preparation of the amide derivatives of the instant products (I) will be apparent to those having ordinary skill in the art and to the extent that the said derivatives are both nontoxic and physiologically acceptable to the body system, the said amides are the functional equivalent of the corresponding [(2-nitro-1-alkenyl)aryloxy1alkanoic acids (1).

The examples which follow illustrate the [(2-nitrol-alkenyl)aryloxy1alkanoic acids, esters and amide deriv atives of the inventioin and the method by which they are prepared. However, the examples are and it will be apparent to those having ordinary skill 1n the art that all of the products embraced by Formula 1, supra, may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.

1.[2,3-dichloro-4- (Z-nitro-l-propenyl) phenoxy] acetic acid Step A: 2,3-dichloro-4-hydroxybenzaldehyde A mixture of 2,3-dichlorophenol (81 g., 0.5 mole), calcium hydroxide (280 g., 3.78 mole), sodium carbonate (320 g., 3.02 mole) and water (2 liters) is placed in a 5 liter round flask equipped with a stirrer, thermometer, reflux condenser and a dropping funnel. The mixture is warmed to 62 C. (internal temperature), the heat is removed and chloroform (719 g., 1.0 mole) is added dropwise over a period of one hour. The temperature remains at about 65 C. during the addition due to heat of reaction. The mixture is heated at 90 C. for one hour and then acidified by addition of concentrated hydrochloric Example illustrative only 8 acid (1300 ml.) while keeping the temperature at 70 C. by external cooling.

Upon cooling to about C. a brown, gummy solid separates; then water is decanted and the residue extracted with hot toluene (500 ml.). The residual water is separated from the toluene solution which then is filtered and concentrated to 150 ml. On cooling, 17.5 g. of crude 2,3-dichloro-4-hydroxybenzaldehyde, M.P. 176-180 C., separates. The product is crystallized from toluene (150 ml.) to obtain 15.6 g. of purified 2,3-dichloro-4-hydroxybenzaldehyde, M.P. 181183.5 C.

Analysis for C7H4C1202: Calculated, C, 44.01; H, 2.11; Cl, 37.12. Found, C, 44.22; H, 2.30; Cl, 37.02.

Step B: Ethyl (2,3-dichloro-4-forrnylphenoxy)acetate A mixture of 2,3-dichloro-4-hydroxybenzaldehyde (32.9 g., 0.172 mole), anhydrous potassium carbonate (38.9 g., 0.39 mole), ethyl bromoacetate (66 g., 0.39 mole) and dimethylformamide (100 ml.) is stirred and heated at 5560 C. for one hour. Upon adding water (300 ml.) a solid separates. The solid is dried and crystallized from cyclohexane (400 ml.) to obtain 42.0 g. (84%) of ethyl (2,3-dichloro-4-formylphenoxy)acetate, M.P. 9l92 C.

Analysis for C H Cl O Calculated, C, 47.68; H, 3.64; Cl, 25.59. Found, C, 47.67; H, 3.58; Cl, 25.40.

Step C: Ethyl [2,3-dichloro-4-(2-nitro-1-propenyl) phenoxy] acetate Ethyl (2,3-dichloro-4-formylphenoxy)acetate (4.88 g., 0.0175 mole) and n-butylamine (0.985 g., 0.0135 mole) are dissolved in dry benzene ml.) and the mixture is heated under a constant water separator until no more water separates. The benzene is evaporated and to the residue is added nitroethane (3.73 g.) and acetic acid (10.4 ml.). The mixture is heated to boiling, cooled and added to ice water. The solid that separates is crystallized from a mixture of parts ethanol and two parts water to obtain 3.36 g. of ethyl [2,3-dichloro-4-(2-nitro-l-propenyl)phenoxy] acetate, M.P. 8888.5 C.

Analysis for C H Cl NO Calculated, 3.92. Found, C, 46.99; H, 3.80.

Step D: [2,3-dichloro-4-(2-nitro-1-propenyl)phenoxy] acetic acid Ethyl [2,3-dichloro-4-(2-nitro l propenyl)phenoxy] acetate (3 g., 0.009 mole) is dissolved in hot acetic acid (16 ml.) and water (12 ml.) and concentrated hydrochloric acid (0.5 ml.) is added. The mixture then is heated and stirred at the boiling point for one hour. On cooling a solid separates. The product is washed with water and crystallized from a mixture of 15 parts acetic acid and 10 parts water to obtain 2 g. of [2,3-dichloro-4-(2-nitro-1 propenyl)phenoxy]acetic acid, M.P. 17l173 C.

Analysis for C H Cl NO Calculated, C, 43.16; H, 2.96; N, 4.58. Found, C, 43.11; H, 3.04; N, 4.45. Example 2.-[2,3-dichloro-4- (2-nitro-1-butenyl) phenoxy] acetic acid Step A: Ethyl [2,3-dichloro-4-(2-nitro-1-butenyl) phenoxy] acetate By following the procedure of Example 1, Step C, but substituting an equimolar amount of l-nitropropane for the nitroethane recited therein, there is obtained ethyl 1 butenyl) phenoxy] ace- [2,3 dichloro 4 (2 nitro tate. Upon recrystallization from a mixture of eight parts acetic acid and one part water the ethyl [2,3-dichloro-4- (2-nitro-l-buteny1) phenoxy] acetate melts at 109-113 C.

Step B: [2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy] acetic acid Ethyl [2,3-dichloro-4- (2-nitro-1-butenyl) phenoxy1acetate (4.41 g.) is added to a mixture of acetic acid (20 ml.), water (14 ml.) and concentrated hydrochloric acid ml.) and the mixture heated to boiling. Hot water then is added to initiate precipitation and the solution is allowed to cool. The solid that separates is crystallized from four parts acetic acid and 3 /2. parts water to obtain 9 2.06 g. of [2,3 -dichloro-4-(2-nitro-1-buteny1)phenoxy] acetic acid, M.P. 135.5-136.5 C.

Analysis for C H Cl NO Calculated, C, 45.02; H, 3.46; N, 4.38. Found, C, 45.22; H, 3.57; N, 4.21.

Example 3.[4-(2-nitro-l-butenyl)-1-naphthyloxy]acetic acid Step A: Ethyl (4-formyl-1-naphthyloxy)acetate A mixture of 4-for1nylnaphthol (13.0 g., 0.0755 mole), potassium carbonate (15.0 g., 0.151 mole), ethyl bromoacetate (25 g., 0.151 mole) and dimethylformamide (75 ml.) is heated at 5560 C. for one hour. The mixture then is worked up as in Example 1, Step B, to obtain 13.2 g. of ethyl (4-formyl-1-naphthyloxy)acetate, M.P. 99100 C. from alcohol. For analysis, one gram of ethyl (4-formyl-1-naphthyloxy)acetate, crystallized two additional times from alcohol, yields a sample of product having a melting point of 100-101.5 C.

Analysis for C H O Calculated, C, 69.75; H, 5.46. Found, C, 69.18; H, 5.58.

Step B: Ethyl [4-(2-nitro-l-butenyl)naphthyloxy]acetate By substituting equimolar amounts of ethyl (4-formyl- 1-naphthyloxy)acetate and l-nitropropane for the ethyl (2,3-dichloro-4-formylphenoxy)acetate and nitroethane recited in Example 1, Step C, and following substantially the procedure described therein the compound ethyl [4- (Z-nitro-l-butenyl)-1-naphthyloxy]acetate is obtained. Upon recrystallization from ethanol the ethyl [4-(2-nitrol-butenyl)-1-naphthyloxy] acetate melts at 117118 C.

Analysis for C H NO Calculated, C, 65.65; H, 5.82. Found, C, 65.85; H, 5.89.

Step C: [4-(Z-nitro-l-butenyl)-1naphthyloxy]acetic acid By substituting ethyl [4-(2-nitro-1-butenyl)-1-naphthyloxy]acetate (4.3 g.) fOr the ethyl [2,3-dichloro4-(2- nitro-1-propenyl)phenoxy]acetate of Example 1, Step D, and following substantially the procedure described therein, the product [4-(2-nitro-1-butenyl)-1-naphthyloxy acid the yield of [4-(2-nitro1-butenyl)-l-naphthyloxy] acetic acid is 2.8 g. and the melting point is 182l 83 C.

Analysis for C H NO Calculated: C, 63.78; H, 5.02; N, 4.65. Found, C, 63.98; H, 5.31; N, 4.64.

Example 4.[2,3-dimethyl-4-(2-nitro-1-propenyl) phenoxy] acetic acid Step A: Ethyl (2,3-dimethylphenoxy)acetate A 500 ml. round-bottom flask is charged with 2,3- dimethylphenol (78 g., 0.64 mole), dimethylformamide (450 ml.), anhydrous potassium carbonate (195 g., 1.4 mole) and ethyl bromoacetate (225 g., 1.34 mole). The stirred reaction mixtur is heated at 60-65 C. in a water bath for 45 minutes and then poured into 1.5 liters of ice water. The product is extracted with ether (500 ml.),

over magnesium sulfate. The ether is distilled at reduced pressure and the product fractionated to give 86 g. (65%) of ethyl (2,3-dimethylphenoxy)acetate, B.P. 153155 C./ 15 mm. The product is used in the next step Without further purification.

Step B: Ethyl [2,3-dimethyl-4-(chloromethyl)phenoxy] acetate A 250 ml. round-bottom flask fitted with a stirrer, condenser and gas inlet tube is charged with ethyl (2,3- dimethylphenoxy)acetate (21 g., 0.1 mole), benzene (40 ml), concentrated hydrochloric acid 25 ml.) and formaldehyde 18 ml. of a 37% aqueous solution). The vigorous- Zene is distilled at reduced pressure and the product is recrystallized from petroleum ether to give 23.5 g. (92%) of ethyl [2,3-dimethyl-4-(chloromethyl)phenoxy]acetate, M.P. 7274 C.

Analysis for C H ClO Calculated, C, 60.82; H, 6.67; Cl, 13,81. Found, C, 61.06; H, 6.61; Cl, 13.58.

Step '0 Ethyl (2,3-dimethyl-4-formylphenoxy)acetate A mixture of ethyl [2,3-dimethyl-4-(chloromethyl) (14.8 g., 0.57 mole), hexamethyleneof ethyl (2,3-dimethyl-4-formylphenoxy)acetate, B.P. -145 C./ 0.05 mm.

Analysis for C H 0 Found, C, 66.43; H, 6.99.

Step D: Ethyl [2,3-dimethyl-4-(Z-nitro-l-propenyl) phenoxy]acetate By following the procedure described in Example 1, Step C, but substituting ethyl (2,3-dimethyl-4-forrnylphenoxy)acetate for the ethyl (2,3-dichloro-4-formylphenoxy)acetate recited therein there is obtained ethyl [2,3-dimethyl-4- Z-nitro- 1 -propenyl )phenoxy] acetate.

Step E: [2,3-dimethyl-4-(2-nitro-1-propenyl)phenoxy] acetic acid By following the procedure of Example 1, Step D, but substituting ethyl [2,3-dimethyl-4-(2-nitro-l-propenyl) phenoxy]acetate for the ethyl [2,3-dichloro-4-(Z-nitro-lpropenyl)phenoxy]acetate described therein there is obtained [2,3-dimethyl-4-(2-nitro 1 propenyl)phenoxy] acetic acid.

Example 5.[4-(2-nitro-l-propenyl)-1-naphthyloxy] acetic acid Step A: Ethyl [4-(2-nitro-1-propenyl)-1-naphthyloxy] acetate Ethyl (4-forrnyl-1-naphthyloxy)acetate (6.1 g., 0.0226

mole) and n-butylarnine (1.65 g., 0.0226 solved in dry benzene (60 ml.) and the mixture 18 heated Calculated, C, 66.08; H, 6.83.

Example '6.-2- [2, 3-dichloro-4- (Z-nitrol-propenyl) phenoxyJpropionic acid Step A: Ethyl 2-(2,3-dichloro-4-formylphenoxy) propionate A mixture of 2,3-dichloro-4-hydroxybenzaldehyde (5.0 g.), ethyl a-bromopropionate (9.2 g.) and potassium carbonate (5.2 g.) in dimethylformamide (25 ml.) is heated at 55-60 C. for 16 hours. The mixture is diluted with water and the solid that separates is crystallized from cyclohexane to obtain 4.6 g. of ethyl 2-(2,3-dichloro-4- formylphenoxy)-propionate, M.P. 67.568.5 C.

Analysis for C I-1 G Calculated, C, 49.51; H, 4.15; Cl, 24.36. Found, C, 49.97; H, 4.57; Cl, 23.78.

Step B: 2-[2,3-dichloro-4-(2-nitro-1-propenyl)phenoxy] propionic acid Ethyl 2 (2,3 dichloro-4-formylphenoxy)propionate (2.0 g.), n-butylamine (0.51 g.) and benzene are refluxed until no more water is distilled. The benzene is evaporated and nitroethane (1.9 g.) and acetic acid (6 ml.) are added to the residue. The mixture is heated to boiling, cooled and extracted with ether. The ether layer then is dried over magnesium sulfate and evaporated and the residual oil is added toacetic acid (15 ml.), water (10 ml.) and concentrated hydrochloric acid (0.5 ml.). The mixture is refluxed for one hour and then poured onto ice. The solid that separates is crystallized from a mixture of one part benzene and one part hexane to obtain a fine solid identified as 2-[2,3-dichloro-4-(2-nitro-1-propenyl)phenoxy]propionic acid which melts at 144- 145 C.

Analysis for C H Cl NO Calculated, C, 45.02; H, 3.46; N, 4.38; Found, C, 44.90; H, 3.59; N, 4.39.

Example 7 .--[2,3-dichloro-4- Z-nitrovinyl) phenoxy] acetic acid By following the procedure described in Example 1, Steps A-D, but substituting an equimolar amount of nitromethane for the nitroethane recited in Example 1, Step C, there is obtained [2,3-dichloro-4-(2-nitrovinyl) phenoxy1acetic acid, M.P. 205.5-206.5 0., upon recrystallization from a mixture of parts acetic acid and 10 parts water.

Analysis for C10H'1C12NO5Z Calculated, C, 41.12; H, 2.42; N, 4.80. Found: C, 41.30; H, 2.71; N, 4.59.

Example 8.--2-[2,3-dichloro-4-(2-nitro-1-butenyl) phenoxylpropionic aci By following the procedure described in Example 6, Steps A and B, but substituting an equimolar amount of l-nitropropane for the nitroethane recited in Step B thereof, the product 2-[2,3-dichloro-4-(2-nitro-1-butenyl) phenoxy]-propionic acid is obtained, M.P. 138-139 (3., upon recrystallization from a mixture of one part benzene and one part hexane.

Analysis for C H Cl NO Calculated, C, 46.72; H, 3.92; N, 4.19; Found: C, 46.75; H, 4.04; N, 4.30.

Example 9.-[2,4-dich1oro-6-(2-nitro-1-butenyl) phenoxy1acetic acid Step A: Ethyl (2,4-dichloro-6-formylphenoxy)acetate of 2,4-dich1oro-6-formylphenol (25.0 g., 0.131 mole), potassium carbonate (26.4 g., 0.19 mole) and ethylbromoacetate (32.0 g., 0.19 mole) in dimethylformamide is heated at 5055 C. for one hour and then diluted with water (300 ml.). The solid that separates is crystallized from a mixture of four parts alcohol and three parts water to obtain 31 g. of ethyl (2,4-dichloro- 6-formylphenoxy)-acetate, M.P. 5253 C.

Analysis for C H Cl Qg Calculated, C, 47.69; H, 3.64; Cl, 25.60. Found: C, 47.65; H, 3.97; Cl, 25.46.

Step B [2,4-dichloro-6-(2-nitro-1-butenyl)phenoxy]- acetic acid Ethyl (2,4 dichloro 6-formylphenoxy)acetate (4.88 g.), n-butylamine (1 g.) and benzene (50 ml.) is refluxed in a water separator until water ceases to be evolved. The benzene is evaporated and acetic acid (10 ml.) and 1- nitropropane (4.5 g.) are added. The mixture is refluxed for 10 minutes. The solvents then are evaporated at reduced pressure and acetic acid ml.), water (14 m1.)

A mixture and concentrated hydrochloric acid (1 ml.) are added. The mixture is refluxed for 48 hours and poured into water. An oil separates and slowly solidifies; The solid is extracted with ten 50 ml. portions of hot cyclohexane and the combined extracts are concentrated to ml. and allowed to cool. The solid that separates melts at .5- C. Upon further extraction with cyclohexane the melting point of the [2,4-dichloro-6-(2-nitro-1-butenyl) phenoxy] acetic acid product is raised to .136-137 v-C. Analysis for C H Cl NO Calculated, C, 45.02;. H, 3.46; N, 4.38. Found: C, 45.12; H, 3.60; N, 4.41.

Example 10.-4-[2,3-dichloro-4-(Z-nitro-l-butenyl) phenoxy1butyric acid Step A: 4-(2,3-dichloro-4-formylphenoxy)butyric acid A mixture of 2,3-dichloro-4-formylphenol (5.73 g., 0.03 mole), ethyl 4-bromobutyrate (11.7 g., 0.06 mole) and potassium carbonate (8.28 g., 0.06 mole) in dimethylformamide (25 ml.) is heated 'at 50-60 C. for 1 /2 hours. Water (50 ml.) is added and the mixture is extracted with ether. The ether extract is dried and evaporated. To the residue is added a solution composed of 48 ml. of 40% sodium bisulfite and 12 ml. of alcohol. The precipitated bisulfite addition compound then is washed with alcohol and ether. The solid is suspended in water and heated in a steam bath. An oily layer of the free aldehyde is formed. The hot water then is decanted and the oily layer is extracted with ether and the ether evaporated. The residue is heated to' 80 C. in a mixture of potassium hydroxide (2.8 g.), methanol (30 ml.) and water (5 ml.), the resulting solution is evaporated to dryness and the residue dissolved in water. Upon acidifi: cation a solid separates. The solid is crystallized from benzene to obtain 2.9 g. of '4-(2,3-dichloro-4-formylphenoxy)butyric acid, M.P. 147148 C.

Analysis for C H C Calculated, C, 47.67;, H,

1 04! 3.64; Cl, 25.59. Found: C, 47.70; H, 3.60; Cl, 25.65.

Step B: 4-[2,3-dichloro-4-(2-nitro-1-butenyl)phenoxy]- butyric acid Example 11.-3-[2,3-dichloro-4-(2-nitro 1 propenyl) phenoxy1propionic acid Step A: 3-(2,3-dichloro-4-formylphenoxy)propionic acid 2,3-dichlono-4 hydroxybenzaldehyde (38.2 g., 0.2 mole) is dissolved in a 10% sodium hydroxide solution (200 -ml.). The solution is heated to boiling and B-propiolactone (144 g., 2.0 moles) is added dropwise at such as rate as to keep the solution boiling. During the addition 10% sodium hydroxide solution is added in portions to maintain an alkaline mixture. Then the solution is cooled and acidified. The precipitated material is dissolved in ether and the product is extracted into a 5% sodium bicarbonate solution. Acidification of the aqueous solution precipitates '3- (2,3-dichloro-4-formylphenoxy)propionic acid, which is purified by recrystallization from ethyl acetate1= Step B: 3- [2,3-dichloro-4-(2-nitro-l-propenyl)phenoxyl propionic acid 1 3 dichloro-4-(2-nitro-1-propenyl)phenoxyJpropionic acid is obtained.

Example 12.[ 2,3 -dimethyl-4-(2-nitro-1-butenyl)phenoxy] acetic acid vA mixture of 2,3-dimethyl-4-hydroxybenzaldehyde (1 g, 0.0081 mole), ethyl bromoacetate (2.7 g., 0.0162 mole) and-potasisum carbonate (2.26 g., 0.0162 mole) in diethyl (2,3-dimethyl-4-formylphenoxy)acetate, (2.0 g.) is refluxed with n-b'utylamine (1.5 g.,; benzene (20 ml.) until water ceases to be evolved (1 /2 hour). The benzene is evaporated and acetic acid (10 ml.) and l-nitropropane (2.0

g.) is added. The mixture Analysis for C H NO Found, C, 60.67; H, 630.

Example 13.[2,4-dichloro-6-(2-nitrovinyl)phenoxy] acetic acid Step A: (2,4 -dichloro-6-formyloxy)acetic acid Ethyl (2,4-dichloro-6-formylphenoxy)acetate (19.0 g.) is dissolved in methanol (100 ml.) containing potassium hydroxide (4.5 g.). The mixture is heated to boiling, and then added to a mixture of acetic acid, water and hydro- Calculated, C, 60.20; H, 6.14.

acid,-M.P. 163165 C.

Analysis for C H Cl O Found, C, 43.80; H, 2.23.

Step B: [2,4-dichloro-6-(2-nitrovinyl)phenoxy] acetic acid (2,4-dichloro-6-formylphenoxy)acetic acid (10 g., 0.04 mole) and n-butylamine (8.8 g., 0.012 mole) in benzene (75 ml.) are refluxed until no more water is evolved (three Calculated, C, 43.40; H, 2.43;

to obtain [2,4-dichloro-6-(Z-nitrovinyl)phenoxy]acetic acid, M.P. 152l53.5 C.

Analysis for C H Cl No z Calculated, C, 41.12; H, 2.42; N, 4.80; Found, C, 41.10; H, 2.63; N, 4.79.

Example 14.[2,4-dichlor-6- (2-nitro-1-propenyl)phenoxyJacetic acid By following the procedure described in Example 13 but substituting nitroethane for the nitromethane recited therein, there is obtained, after crystallization from a mixture of ligroinbenzene, methyl cyclohexane and n-butyl [2,4-dichloro-6-(2nitro-l propeny1)phenoxy] acetic acid, M.P. 1l3.5114 C.

Analysis for C H Cl NO Calculated, C, 43.16; H, 2.96; N, 4.58; Found, C, 43.37; H, 3.10; N, 4.57.

Example l5.[2,3-dichloro-4-(2-nitro-l oxyJacetic acid Step A: (2,3-dichloro-4-formylphenoxy)acetic acid heptenyl phen- The mixture is heated to boiling, poured into water and the solution acidified. The solid that separates is crystallized from acetonitrile to obtain 12.4 g. of (2,3-dichloro-4-formylphenoxy)acetic acid, M.P. 207-210 C.

Step B: [2,3-dichloro-4-(2-nitro-1-heptenyl)phenoxy] acetic acid By substituting equimolar amounts of (2,3-dichloro-4- formylphenoxy)acetic acid and l-nitrohexane for the (2, 4-dichloro-6-formylphenoxy) acetic acid and nitromethane of Example 13 and following substantially the procedure therein, there is obtained [2,3-dichloro-4-(2- nitro-l-heptenyl)phenoxy]acetic acid, M.P. 132133 C. from methylcyclohexane.

Analysis for C H Cl NO Calculated, C, 49.74; H, 4.73; N, 3.87; Found, C, 49.84; H, 4.73; N, 3.90.

16.[2,3-dichloro-4-(2-nitro-1-hexenyl)phenoxy] acetic acid Example methyl [2,3-dichloro-4-(2-nitro 1 propenyl)phenoxy] acetate, M.P. l18119 C.

Analysis for C H Cl NO Calculated, C, 45.02; H, 3.46; N, 4.28; Found, C, 45.17; H, 3.36; N, 4.17.

Example l8. [2,3-dichloro-4- 2-nitrol-propenyl) phenoxy] acetamide benzene and hexane to (50 ml.) and acetonitrile (1 ml.) gives 580 mg. of [2,3-dichloro-4-(2-nitro-1-propenyl)phenoxy] acetamide, M.P. 16l.5162 C. in 13.8% yield.

Analysis for C H Cl N O Calculated, C, 43.30; H, 3.31; CI, 23.24. Found, C, 43.43; H, 3.23; Cl, 23.12.

In a manner similar to that described in Example 1, Steps B, C and D, supra, for the preparation of [2,3-dichloro-4-(Z-nitro-l-propenyl)phenoxy]acetic acid, all of the [(Z-nitro-l-alkenyl)aryloxylalkanoic acid products (I) of the invention may be obtained. Thus, by substitutthat example, all of the [(2-nitro-l-alkenyl)aryloxy]alkanoic acid products (I) of the invention may be obtained.

ple 1, Steps B, pict the nuclear hydroxybenzaldehyde, alkyl haloalkanoate, nitroalkane or aryl substituted nitroalkane starting the compounds of this invention by conventional methods materials of the process and the corresponding products and, if desired, can be made up as e-lixirs or as injectable produced thereby: solutions by methods well-known to pharmacists.

It is also within the scope of this invention to combine X3 X2 two or more of the compounds of this invention in a unit Base dosage form or to combine one or more of the compounds OCH OH XPYPCOORA -with other known diuretics and saluretics or with other i desired therapeutic and/or nutritive agents in dosage unit orm. X3 X2 The following example is included to illustrate the preparation of a representative dosage form: 001t- OY CO0R 1 Example 30.-Dry-filled capsules contarnmg mg. of X5 X6 active ingredient per capsule i Per capsule (mg) R NHnl [2,3-dichloro-4-(2-nitro-1-propenyl)- phenoxy1acetic acid 20 RCHzNOl I Lactose 174 Magnesium stearate 6 Capsule size No. 1 200 20 l The [2,3 dichloro-4-(2-nitro 1 propenyl)phenoxy] nc=0 -().-YL-COOR4 acetic acid is reduced to a No. 60 powder and then lactose 1 l and magnesium stearate are passed through a No. 60 5 5 bolting cloth onto the powder and the combined ingredients admixed for 10 minutes and then filled into No. Hydrolysis l 1 dry gelatin capsules.

Similar dry-filled capsules can be prepared by replacing the active ingredient of the above example by any of the other novel compounds of this invention. (FYPGOOH It will be apparent from the foregoing description No, I that the [(2-nitro-1-alkenyl)aryloxy1alkanoicacid products (I) of this invention constitute a valuable class of TABLE 1 Ex. R R l R 4 X Z X 3 X 5 X 6 Y 1 19- -CH2 -'(CH2)sCH3 -'C2H5 C1 C1 H H -(CH2);

-onn 412115 -on. a H -on, -CHz- H. -(CH2)4CHa --'CH3 CH2 --CH3 -CHa -CH3 -CH2- '(CHz)4CH3 -(CH2)aCH3 -CH3 H --CH3 -CH3 H -(CH2)3- C2H5 -CH3 CZH5 -(CH2)4-' Ii 11 -Cl'Ig-- -CH3 -(CH2)2CH3 -'C4Hn --CH2 CH3 H H (CHz) (CH2)zCHs -ozH5 or or n H -oH2- 26. --C2H5 -'(CH2)aCHa -CHa --CHa H H -0Ha -CHCHs- -CH3 -(OHZ)ZCHK -CH3 cH=oH-oH=CH- H 11 CHCH; CH3 -'(CH2)aCHa --CzH5 --(CH2)4- H H -CHz- --on; --Q -03H1 -o113 -or13 H -o113 c1r2 The products of the invention are diuretic and saluretic compounds which have not been prepared heretofore. agents which can be administered in a wide variety of One skilled in the art will also appreciate that the proctherapeutic dosages in conventional vehicles as, for examesses disclosed in the above examples are merely illusple, by oral administration in the form of a tablet as trative and are capable of a wide variation and modifiwell as by intravenous injection. Also, the dosage of the cation without departing from the spirit of this invention. products may be varied over a wide range as, for exam- What is claimed is:

ple, in the form of scored tablets containing 5, 10, 25, 1. A member selected from the group consisting of a 50, 100, 150, 250 and 500' milligrams of the active ingrecompound having the formula:

dient for the symptomatic adjustment of the dosage to (mm the patient to be treated. RC=CH I A suitable unit dosage form of the products of this l lo: 1 2u invention can be administered by mixing 20 mg. of a l y yl acid a Suitwherein R is a member selected from the group conable acid addition salt, ester or amide derivative thereof, i i f h d and 1ower alkyl; the X radicals are with 174 mg. of lactose and 6 mg. of magnesium stearate similar or dissimilar members selected from the group and placing the 200 mg. mixture into a No. 1 gelatin consisting of halogen, lower alkyl and, taken together, capsule. Similarly, by employing more of the active intwoX radicals on adjacent carbon atoms of the benzene gredient and less lactose, other dosage forms canbe put ring may be joined to form an hydrocarbylene chain up in No. l gelatin capsules and, should it be necessary containing from three to four carbon atoms between their to mix more than 200 mg. of ingredients together, larger points of attachment; m is an integer having a value of capsules may be employed. Compressed tablets, pills or two to four and n is an integer having a value of one to other desired unit dosages can be prepared to incorporate three; and the nontoxic, pharmacologically acceptable 17 salts, lower alkyl esters and amide derivatives thereof.

2. A compound having the formula:

to three.

3. A compound having the formula:

wherein R is lower alkyl; X and X are halogen and n is an integer having a value of one to three.

4. A compound having the formula:

R(|J=CH- N 2 wherein R is lower alkyl; X and X are lower alkyl and n is an integer having a value of one to three.

5. A compound having the formula:

4 (2-nitro-1-propenyl)phenoxy] 1 butenyl)phenoxy] 4 (2 nitrO-l-butenyDphenoxy] hexenyl phenoxy] -propeny1) phebutenyl) -5, 6,7, S-tetrahydro-L References Cited J. American Chemical Society, vol. Worrall, pp. 1556 to 1558 relied on.

Advanced Organic Chemistry, by Royals (1961), pp. 600 to 601 relied on.

LORRAINE A. WEINBERGER, Primary Examiner. L. THAXTON Assistant bxammer. 

